Landogrozumab

Transforming growth factor-β superfamily members, such as myostatin, growth/differentiation factor 11, and activin A, negatively regulate skeletal muscle mass. Inhibitors targeting these cytokines or activin receptor type IIB have the potential to treat muscular diseases and enhance physical performance. However, because of their effects on muscle mass and potential misuse, they are strictly prohibited in sports. Given the high potential for misuse as a doping agent in sports, effective analytical methods for these prohibited antibodies targeting these specific cytokines or their receptor are critically needed. In this study, we aimed to develop and validate a multitarget method to detect the prohibited transforming growth factor-β superfamily-targeting monoclonal antibodies, such as landogrozumab, domagrozumab, and the activin receptor type IIB-targeting antibody, bimagrumab, in human plasma and dried blood spot (DBS) samples using liquid chromatography-tandem mass spectrometry. Antibodies were purified from both the DBS and plasma samples using protein G magnetic beads and field-asymmetric ion mobility spectrometry (FAIMS) to minimize interference, followed by liquid chromatography-tandem mass spectrometry analysis. The validation process included tests for specificity, selectivity, linearity, limit of detection (LOD), limit of identification, precision, recovery, carryover effect, and matrix effect. The LODs for the target antibodies were identical in both DBS and plasma samples at 0.1 µg/mL for landogrozumab heavy and light chains, as well as 0.25 µg/mL for the domagrozumab light chain and 0.25 µg/mL for the bimagrumab heavy chain. However, the heavy chain of domagrozumab exhibited an LOD of 0.5 µg/mL in DBS and 1 µg/mL in plasma. The analytical method demonstrated strong linearity, with R² values greater than 0.99 for both plasma and DBS, and no carryover effect. Precision (CV%) was below 15 % at both middle (1 or 5 µg/mL; specific to the heavy chain of domagrozumab in plasma) and high (10 µg/mL) concentrations and was less than 20 % at the LOD. The selectivity and specificity indicated no interference in the analysis of target mAbs in different blood samples. Recovery was 31.6-49.8 % for DBS and 51.4-85.3 % for plasma, with no significant matrix effect. This study provides an effective method for doping analysis and novel protein detection.

Cachexia is a formidable clinical challenge in pancreatic cancer. We assessed LY2495655 (antimyostatin antibody) plus standard‐of‐care chemotherapy in pancreatic cancer using cachexia status as a stratifier.

In this randomized, phase 2 trial, patients with stage II–IV pancreatic cancer were randomized to 300 mg LY2495655, 100 mg LY2495655, or placebo, plus physician‐choice chemotherapy from a prespecified list of standard‐of‐care regimens for first and later lines of care. Investigational treatment was continued during second‐line treatment. The primary endpoint was overall survival.

Overall, 125 patients were randomized. In August 2014, 300 mg LY2495655 was terminated due to imbalance in death rates between the treatment arms; in January 2015, 100 mg LY2495655 treatment was terminated due to futility. LY2495655 did not improve overall survival: the hazard ratio was 1.70 (90% confidence interval, 1.1–2.7) for 300 mg vs. placebo and 1.3 (0.82–2.1) for 100 mg vs. placebo (recommended doses). Progression‐free survival results were consistent with the overall survival results. A numerically higher hazard ratio was observed in patients with weight loss (WL) of ≥5% (cachexia) than with <5% WL within 6 months before randomization. Subgroup analyses for patients stratified by WL in the 6 months preceding enrollment suggested that functional responses to LY2495655 (either dose) may have been superior in patients with <5% WL vs. patients with ≥5% WL. Among possibly drug‐related adverse events, fatigue, diarrhoea, and anorexia were more common in LY2495655‐treated than in placebo‐treated patients.

In the intention‐to‐treat analysis, LY2495655 did not confer clinical benefit in pancreatic cancer. Our data highlight the importance of assessing survival when investigating therapeutic management of cachexia and support the use of WL as a stratifier (independent of performance status).